The present invention relates to apparatus and methods for delivering drugs and other beneficial agents. More specifically, the present invention relates to apparatus and methods for subcutaneous, transdermal, intravenous, and intramuscular delivery of drugs and other beneficial agents to a subject.
In an effort to improve the convenience of drug delivery, provide accurate dosing, and improve efficacy, various invasive and non-invasive drug delivery systems have been devised. The many techniques for delivering drugs include direct injection into body tissues, oral administration, intravenous administration, and transdermal delivery through the skin. As used herein, transdermal delivery means introduction of drugs or other beneficial agents through, or by way of, the skin. Except in the case of transdermal delivery, the above-mentioned drug delivery systems typically provide for systemic administration of drugs in that the drug is delivered throughout the body by the bloodstream. In the case of transdermal delivery, passive diffusion and active transport mechanisms can be used for more localized delivery of drugs into the tissues.
Each type of drug delivery system has its own advantages over the various other delivery technologies. Most recently, transdermal drug delivery has been shown to offer particular promise for a number of reasons. As an alternative to medicines administered orally, transdermal drug delivery avoids the xe2x80x9cfirst-passxe2x80x9d metabolism of the liver, allowing for relatively lower doses and more controlled delivery of conventional forms of certain drugs. In contrast to the direct injection of drugs, transdermal drug delivery allows for continuous and convenient drug administration over an extended time period. Transdermal delivery techniques can, in some applications, allow a subject unrestricted mobility, a benefit not afforded by many intravenous drug administration systems.
The low permeability of the outer surface of mammalian (including human) skin, however, provides a formidable barrier to the transdermal administration of drugs at therapeutic levels. The skin""s outermost layer, the epidermis, acts as the primary resistive barrier to drug diffusion. The epidermis can be most basically described as an avascular layer of stratified squamous keratinised epithelium sitting on a basement membrane. The epithelium can be sub-divided into four primary layers from the base to the free surface. The most resistive layer of the epidermis forms a superficial water-resistant protective layer called the stratum corneum. The stratum corneum is composed of layers of dead tissue, essentially consisting of flattened cells filled with cross-linked keratin together with an extracellular matrix made up of lipids arranged largely in bilayers. Underlying the stratum corneum are the further layers of the epidermis, generally comprising three layers commonly identified as the stratum granulosum, stratum spinosum, and stratum basale. These further layers of the epidermis are followed by the dermis, which contains two layers, the papillary dermis and the reticular dermis.
One class of techniques for overcoming the resistive barriers imposed by intact skin is assisted diffusion of a drug through the epidermis by xe2x80x9celectrotransportxe2x80x9d processes. Using the principles of electrotransport, a direct electrical current or an electrical potential gradient is used to actively transport the drug transcutaneously into the body. The composition of the stratum corneum, however, is such that its innate resistance to the flow of electrons is relatively high in comparison to other underlying body tissue (e.g., the further layers of the epidermis and the blood vessels therein).
Electrotransport processes are presently used in a wide variety of therapeutic drug delivery applications. One method of using electrotransport for transdermal drug delivery is known as xe2x80x9ciontophoresis.xe2x80x9d In iontophoresis, the diffusion of an ionized drug (e.g., salts of a pharmaceutical or other drug which, when dissolved, form charged ions) across the stratum corneum and into the dermal layers a skin surface is enhanced by the direct application of a mild electrical potential to the skin. Typically, the permeation rate (or xe2x80x9cfluxxe2x80x9d) of the ionized drug compound will be directly proportional to the strength of the applied electric current. A second type of electrotransport process called xe2x80x9celectroosmosis,xe2x80x9d involving the transdermal flux of a liquid solvent containing an uncharged drug or pharmaceutical agent, has been recognized as a means for delivery of an uncharged drug or agent into the body. Electroosmosis, in which the solvent convectively moves through a xe2x80x9ccharged porexe2x80x9d in response to the preferential passage of counter ions, can be induced by the presence of an electric field imposed across the skin by the active electrode of an iontophoretic device. A third type of electrotransport is known as xe2x80x9celectroporation.xe2x80x9d Electroporation can be used for drug or other agent transport by altering lipid bilayer permeability through the formation of transiently existing pores in the skin membranes.
At any given time during electrically assisted drug or agent delivery, more than one of these electrotransport processes may be occurring simultaneously to some extent.
As illustrated by FIG. 1, a typical iontophoretic system 16, similar to the iontophoretic system disclosed in U.S. Pat. No. 5,618,265 to Meyers et al., involves the placement of two oppositely charged xe2x80x9cdonor and counterxe2x80x9d electrodes (an anode and a cathode) 18, 20 on a subject""s skin surface 30 at or around a tissue region selected for therapeutic application. A reservoir 22 containing the ionized drug to be delivered is placed under the electrode bearing the same charge as the drug (the xe2x80x9cdonor electrodexe2x80x9d). Thus, in anodal iontophoresis, as is shown in FIG. 1, a positively charged drug is placed under the positively charged anode electrode 18. Conversely, if the ionized drug to be delivered were negatively charged, then the negative electrode (cathode) 20 would be the active electrode under which the ionized drug would be placed. An ion-conducting adhesive 28 may be situated under each electrode 18, 20 for stabilization of the electrodes. Electrolytes are typically added-to the solution containing the ionized drug so that current can be easily conducted. A selectively permeable membrane (not shown) may further be placed under the active electrode 18 to allow for selective flow of particular types of charged and uncharged species into skin surface 30. A voltage source 24, typically a battery, supplies direct electric current by conductive wires 26 extending to the electrodes. At electrodes 18, 20, the current is converted to an ionic current by a series of oxidation-reduction reactions.
To activate the system, electrodes 18, 20 are spaced apart from one another on skin surface 30 where skin surface 30 acts as a conductor to complete the electrical circuit of iontophoretic system 16. Upon activation of iontophoretic system 16, the charged drug is repelled by active electrode 18 into the skin 30 (as indicated by the arrows), thereby initiating drug transport by electrostatic repulsion, ionic conduction, and other cooperating electrotransport processes.
Representative iontophoretic systems are disclosed in U.S. Pat. No. 5,618,265 to Myers et al. and U.S. Pat. Nos. 5,647,844 and 4,927,408 to Haak et al. Other patents discussing a variety of iontophoresis systems, iontophoresis electrodes, and/or methods of iontophoretically administering medicament ions include U.S. Pat. Nos. 4,744,787 to Phipps et al., U.S. Pat. No. 4,752,285 to Petelenz et al., U.S. Pat. No. 4,820,263 to Spevak et al., U.S. Pat. No. 4,886,489 to Jacobsen et al., U.S. Pat. No. 4,973,303 to Johnson et al., and U.S. Pat. No. 5,125,894 to Phipps et al.
Modern galvanic transdermal delivery systems have been disclosed in U.S. Pat. No. 5,618,265 to Myers et al. and U.S. Pat. Nos. 5,647,844 and U.S. Pat. No. 4,927,408 to Haak et al. Myers et al. and Haak et al. generally discuss forming the counter and donor electrodes of dissimilar metals or materials with different half cell reactions. The electrode materials discussed generally include a zinc anode and silver chloride cathode. The voltage generated by the zinc and silver chloride galvanic couples of the references is, however, only about 1 volt, a level insufficient to assist in the therapeutic transdermal delivery of many drugs and other beneficial agents.
Although other transport mechanisms such as electroporation and electroosmosis are involved in the movement of the charged drug through the skin, the efficacy of this process depends largely upon ionizable pharmaceuticals or other drugs. Compounds which are hydrophobic and/or which have a relatively high molecular weight (e.g., many peptide and protein drugs) are less susceptible to iontophoretic delivery. Additionally, the physiological pH of human skin is between 3 and 4, thus causing the surface of the skin to be negatively charged due to a preponderance of carboxylic acid functionalities of negatively charged amino acid residues. As a result of this net negative charge, the skin functions as a selective membrane in allowing the transport of positively charged drug species to proceed with less resistance than the transport of negatively charged drug species. (Burnette and Ongpipattanakul, 1987). Peptide and protein drugs are particularly affected by pH, which exerts a major influence on their isoelectric point. Thus, the characteristic charge associated with an ionizable drug in conjunction with the pH of the skin may render certain drugs more susceptible to iontophoretic transport than others. Also influencing the effectiveness of iontophoretic delivery are many complicating factors that vary with age, gender, race, site of iontophoretic delivery, and skin characteristics of particular individuals (e.g., skin quality, skin follicle density, etc.). The interface between an electrode and the skin can act as a further limiting factor such as when the surface contact of an electrode is poor, or when the skin tissue is dry and clean. Finally, the transdermal delivery of many drugs requires that the iontophoretic apparatus be configured to achieve a xe2x80x9cskin breakthrough voltagexe2x80x9d of a particular threshold to initially overcome the rigorous impedance barrier of the stratum corneum. Once the impedance barrier of the stratum corneum has been broken down by the xe2x80x9cskin breakthrough voltage,xe2x80x9d a follow-on voltage of a much lesser intensity is capable of continuing the transdermal facilitation of the drug across the skin barrier. The need for a xe2x80x9cskin breakthrough voltagexe2x80x9d in the transdermal application of many drugs limits the usefulness of many prior art galvanic iontophoretic devices, which are typically configured as relatively low voltage systems.
Currently, there has been a renewed interest in the use of the various transdermal delivery systems, due mainly to the widespread acceptance of passive transdermal patches and recent breakthroughs in recombinant DNA technology leading to the discovery of a large number of therapeutically important peptides and proteins. Accordingly, a need exists for an improved electrotransport system that overcomes the resistive properties of the skin while overcoming many, if not all, of the aforementioned drug delivery problems associated with conventional iontophoretic techniques.
The invention includes apparatus and methods for electrically assisted transport (xe2x80x9celectrotransportxe2x80x9d) of a drug or other beneficial agent through a skin or mucosal membrane surface, wherein at least one of the cathode or anode electrode of an electrochemical cell is configured, at least in part, as an electroactive needle adapted to be inserted all or part way through the stratum corneum of a subject""s skin, resulting in direct current flowing from the electroactive needle through the tissues of the subject. As used herein, a xe2x80x9csubjectxe2x80x9d will typically be a mammal.
The direct current generated by the apparatus of the present invention bypasses the cutaneous keratin layer of the skin, resulting in enhanced transdermal delivery of a drug or other beneficial agent into the tissues underlying and/or surrounding the electroactive needle(s). A reservoir containing a drug or other beneficial agent may be provided in fluid communication with one or more electroactive needles, in which case the electroactive needle(s) may be configured with a hollow bore interior extending therethrough for transport of the drug or other beneficial agent directly into a subject""s tissues. The drug or other beneficial agent is preferably provided as a liquid or dissolved in a fluid or solvent such that it is otherwise in liquid form. In a related embodiment, the electroactive needle of the present invention may be configured of a length and shape suitable for intravenous and/or intramuscular delivery of a drug or other beneficial agent.
An apparatus of the present invention for transdermal, intradermal and/or subcutaneous delivery of a drug or other beneficial agent includes an electrochemical cell having an electrochemically active cathode and an electrochemically active anode wherein at least a portion of at least one of the cathode and anode is configured as at least one electroactive needle.
The present invention also includes a method of electrically facilitating the transport of a drug or other beneficial agent through body tissues of a subject. The method comprises providing an anode configured to conduct current in relation to a first skin surface, providing a cathode and an anode configured to conduct current in relation to a respective skin surfaces wherein at least a portion of at least one of the cathode and anode are configured as at least one electroactive needle of a predetermined length, providing at least one conductor extending between and electrically interconnecting the anode with said cathode, providing a drug or other beneficial agent reservoir disposed adjacent and in fluid communication with an electrically conducting area of at least one of the anode and the cathode, inserting the electroactive needle a predetermined distance into a skin surface to electrochemically activate the anode and cathode, electrochemically generating a voltage from the activation of the anode and the cathode, and delivering voltage to the body tissues of a subject to facilitate the transport of a drug other beneficial agent though the body tissues of the subject.
In a multi-needle embodiment of the present invention, the cathode and/or anode may be formed of a plurality of electroactive needles.
The electrotransport apparatus of the present invention may further include a battery, power cell, or one or more additional electrochemical cells, to boast the voltage of the apparatus. A resistor can be added to control the voltage flow. The device can be further configured to deliver medication contained in standard medication cartridges.
As a further embodiment, an implantable electrotransport system is disclosed wherein one of the anode or cathode of an electrochemical cell is implanted under a skin surface. In a preferred embodiment, the implantable electrode is configured as a porous or micro-porous metal substrate which allows drugs or other beneficial agents to flow therethrough. A battery and resistor may be provided to enhance the performance of the device.
The present invention also includes a porous or micro-porous metal substrate electrode, comprising either the anode or the cathode of an electrochemical cell, mounted on a skin surface for the electrically assisted delivery of drugs or other beneficial agents through the skin.
In a still further embodiment, an electrotransport system having active porous electrodes is disclosed wherein the electrotransport system is entirely implantable under a skin surface.